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Rituximab Maintenance for 2 Years in Patients with High Tumour Burden

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Rituximab Maintenance for 2 Years in Patients with High Tumour Burden Articles Rituximab maintenance for 2 years in patients with high tumour burden follicular lymphoma responding to rituximab plus chemotherapy (PRIMA): a phase 3, randomised controlled trial Gilles Salles, John Francis Seymour, Fritz Off ner, Armando López-Guillermo, David Belada, Luc Xerri, Pierre Feugier, Réda Bouabdallah, John Vincent Catalano, Pauline Brice, Dolores Caballero, Corinne Haioun, Lars Moller Pedersen, Alain Delmer, David Simpson, Sirpa Leppa, Pierre Soubeyran, Anton Hagenbeek, Olivier Casasnovas, Tanin Intragumtornchai, Christophe Fermé, Maria Gomes da Silva, Catherine Sebban, Andrew Lister, Jane A Estell, Gustavo Milone, Anne Sonet, Myriam Mendila, Bertrand Coiffi er, Hervé Tilly Summary Lancet 2010; 377: 42–51 Background Patients with follicular lymphoma can have long survival times, but disease progression typically occurs Published Online 3–5 years after initial treatment. We assessed the potential benefi t of 2 years of rituximab maintenance after fi rst-line December 21, 2010 treatment in patients with follicular lymphoma receiving a rituximab plus chemotherapy regimen. DOI:10.1016/S0140- 6736(10)62175-7 Methods The randomised, open-label PRIMA study was undertaken in 223 centres in 25 countries. 1217 patients with See Comment page 4 previously untreated follicular lymphoma needing systemic therapy received one of three non-randomised Hospices Civils de Lyon, Université Claude Bernard, immunochemotherapy induction regimens used in routine practice. 1019 patients achieving a complete or partial UMR CNRS5239, Pierre-Bénite, response were then randomly assigned to receive 2 years of rituximab maintenance therapy (375 mg/m² every 8 weeks) France (Prof G Salles MD, or observation. Treatment was assigned equally by centralised block randomisation, stratifi ed by induction regimen, Prof B Coiffi er MD); Peter response, region, and centre. Neither the participants nor those giving the interventions, assessing outcomes, and MacCallum Cancer Centre and University of Melbourne, analysing data were masked to group assignments. The primary endpoint was progression-free survival (PFS). Analysis Melbourne, VIC, Australia was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00140582. (Prof J F Seymour FRACP); Ghent University, Ghent, Belgium Findings 505 patients were assigned to rituximab maintenance and 513 to observation (one patient died during (Prof F Off ner MD); Hospital Clinic, Barcelona, Spain randomisation). With a median follow-up of 36 months (IQR 30–42), PFS was 74·9% (95% CI 70·9–78·9) in the (A López-Guillermo MD); Charles rituximab maintenance group (130 patients progressed) and 57·6% (53·2–62·0) in the observation group University in Prague, Faculty of (218 progressed; hazard ratio [HR] 0·55, 95% CI 0·44–0·68, p<0·0001). 2 years after randomisation, 361 patients (71·5%) Medicine, University Hospital in the rituximab maintenance group were in complete or unconfi rmed complete response versus 268 (52·2%) in the Hradec Králové, Prague, Czech Republic (D Belada MD); Institut observation group (p=0·0001). Overall survival did not diff er signifi cantly between groups (HR 0·87, 95% CI Paoli Calmettes, Marseille, 0·51–1·47). Grade 3 and 4 adverse events were recorded in 121 patients (24%) in the rituximab maintenance group France (Prof L Xerri MD, and 84 (17%) in the observation group (risk ratio 1·46, 95% CI 1·14–1·87; p=0·0026). Infections (grades 2–4) were the R Bouabdallah MD); CHU de most common adverse event, occurring in 197 (39%) and 123 (24%) patients, respectively (risk ratio 1·62, 95% CI Nancy, Université Henri Poincaré, Nancy, France 1·35–1·96; p<0·0001). (Prof P Feugier MD); Frankston Hospital, Frankston, VIC, Interpretation 2 years of rituximab maintenance therapy after immunochemotherapy as fi rst-line treatment for Australia (J V Catalano FRACP); follicular lymphoma signifi cantly improves PFS. Hôpital Saint-Louis, AP-HP, Paris, France (P Brice MD); Universitario de Salamanca, Funding Groupe d’Etude des Lymphomes de l’Adulte (GELA) and F Hoff mann-La Roche. Salamanca, Spain (D Caballero MD); Hôpital Henri monoclonal antibody rituximab with various chemo- Mondor, AP-HP, Créteil, France Introduction (Prof C Haioun MD); Odense Follicular lymphoma is the second most common therapy regimens can improve patients’ overall survival, University Hospital, Odense, lymphoma subtype and, despite substantial improve- and this combination is now regarded as the standard of Denmark (L M Pedersen MD); ments in survival, disseminated disease is usually care in fi rst-line follicular lymphoma. CHU de Reims, Reims, France incurable.1,2 The disease characteristically responds well Rituximab, in view of its effi cacy, pharmacokinetic (Prof A Delmer MD); North Shore Hospital, Auckland, New to fi rst-line therapy but typically manifests repeated characteristics, and safety profi le, has already been Zealand (D Simpson FRACP); relapses with the need for recurrent therapeutic investigated as maintenance treatment in patients with Helsinki University Central interventions, with disease-free intervals becoming follicular lymphoma.9–13 Previous studies have shown a Hospital, Helsinki, Finland 3,4 (S Leppa MD); progressively shorter. Although some patients can signifi cant clinical benefi t of rituximab maintenance in Institut Bergonié and initially be managed with watchful waiting because they patients with relapsed disease after chemotherapy with Université Victor Segalen are asymptomatic with no adverse prognostic features, or without rituximab.11,12 The use of rituximab Bordeaux 2, Bordeaux, France most need systemic cytotoxic-based treatment. In the maintenance has also been studied after initial (Prof P Soubeyran MD); 5–8 9,10 Academic Medical Centre, past decade, several randomised studies have treatment with single-agent rituximab or chemo- established that the combination of the anti-CD20 therapy alone;13 however, neither of these induction 42 www.thelancet.com Vol 377 January 1, 2011 Articles regimens is considered optimum as initial treatment suitable than 3 months to reach a trough in serum Amsterdam, Netherlands for patients in need of therapy. Hence, the PRIMA rituximab concentration of 25 μg/mL.14,15 Randomisation (Prof A Hagenbeek MD); CHU de Dijon, Dijon, France (Primary RItuximab and MAintenance) study was was stratifi ed for induction regimen, response to induction (O Casasnovas MD); designed to assess the potential benefi t of 2 years of treatment, geographical region, and centre, with a block Chulalongkorn University, rituximab maintenance after fi rst-line treatment in size of four. Investigators enrolled the participants, and Bangkok, Thailand patients with follicular lymphoma receiving a rituximab assignment to trial groups was done with a computer- (Prof T Intragumtornchai MD); Institut de Cancérologie plus chemotherapy regimen. assisted randomisation allocation sequence (generated by Gustave Roussy, Villejuif, a statistician) that took place centrally at Groupe d’Etude France (C Fermé MD); Methods des Lymphomes de l’Adulte (GELA) central offi ces with a Portuguese Institute of Study design and patients fax process, without the intervention of investigators. Oncology, Lisbon, Portugal (M G da Silva MD); Centre Léon This open-label, international, multicentre randomised Neither the participants nor those giving the interventions, Bérard, Lyon, France study was undertaken between December, 2004, and assessing outcomes, and analysing data were masked to (C Sebban MD); Centre for April 2007, in 223 centres in 25 countries. The trial group assignment. Medical Oncology, Barts and consisted of two phases, induction and maintenance. the London School of Medicine and Dentistry, Queen Mary Patients were eligible for induction if they were older Procedures University of London, London, than 18 years and presented with untreated follicular Initial staging included physical examination; standard UK (Prof A Lister MD); Concord lymphoma (grade 1, 2, or 3a) diagnosed by a lymph-node laboratory assessments; CT scans of the chest, abdomen, Hospital, Concord, NSW, biopsy (done within 4 months of study registration). and pelvis; and bone marrow biopsy. Pathological specimens Australia (J A Estell FRACP); Fundaleu, Buenos Aires, Eligibility required at least one criterion of high tumour were centrally reviewed by a panel of expert pathologists in Argentina (G Milone MD); UCL, burden—namely, bulky disease (one lymphoma lesion each country or in the GELA pathology centre. Mont-Godinne, Yvoir, Belgium greater than 7 cm); three separate nodes of 3 cm or more; During the induction phase, patients were treated with (A Sonet MD); symptomatic splenic enlargement; organ compression by one of three standard immunochemotherapy regimens, F Hoff mann-La Roche, Basel, Switzerland (M Mendila MD); tumour, pleural, or peritoneal eff usion; raised serum with each centre selecting the preferred regimen for all and Centre Henri Becquerel, concentrations of either lactate dehydrogenase or patients enrolled in that centre. The three chemotherapy Rouen, France (Prof H Tilly MD) β2-microglobulin; or the presence of B symptoms. Patients regimens combined with rituximab were: CVP (cyclo- Correspondence to: had to have a performance status of 2 or less on the Eastern phosphamide 750 mg/m² given intravenously on day 1, Prof Gilles Salles, Hospices Civils Cooperative Oncology Group (ECOG) scale and adequate vincristine 1·4 mg/m² [capped at 2 mg] given de Lyon, Université Claude Bernard, UMR CNRS5239, haematological function (unless due
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